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A Novel Method for the Esterification of N-Protected Amino Acids

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Title: A Novel Method for the Esterification of N-Protected Amino Acids
Authors: Ueda, Kazuo
Issue Date: 31-Jul-1992
Citation: 長崎大学教養部紀要. 自然科学篇. 1992, 33(1), p.1-6
Abstract: A mild and simple procedure for the esterification of N-protected amino acids is described involving room temperature reaction of N-hydroxysuccinimide esters of a variety of N-protected amino acids with alcohols in the presence of 4-(N, N-dimethylamino)-pyridine. In this manner a depsipeptide was also prepared in high yield. Mild and simple esterification procedures are of considerable interest in the synthesis and manipulation of many natural products. Esters of N-protected amino acids are useful intermediates not only for the peptide synthesis, but also for the preparation of amino aldehydes. The carboxyl group of amino acids is commonly protected as an alkyl ester during peptide synthesis, for which the use of methyl, ethyl, benzyl, and tert-butyl esters is well-documented. The preparation of esters of N-protected amino acids is most often effected by alkylation with an alkyl halide of the triethylammonium or cesium salt of the corresponding carboxylate ion. Recently the use of 4-(N, N-dimethyl-amino) pyridine (DMAP) as catalyst for carbodiimide mediated esterification of N-protected amino acids has been reported. The author now reports that esters of N- protected amino acids are easily obtained in high yields and stereochemically pure form by reaction of the corresponding N-hydroxysuccinimide esters with the alcohols in the presence of DMAP under mild conditions as shown below: The N-hydroxysuccinimide esters of N-protected amino acids are readily available and well used as active ester for acylation reaction. The esters of N-protected amino acids were prepared in high yields by the treatment of the N-hydroxysuccinimide ester of N-protected amino acid with 1.5 equivalent of the appropriate alcohol and 1 equivalent of DMAP in CH2CI2 at room temperature for 6 h. The esters (1-8) prepared by this method are summarized in Table 1. Both N-benzyloxycarbonyl and N-tert-butyloxycarbonyl amino acids readily undergo estenfication with methanol, ethanol, or benzyl alcohol to furnish the corresponding esters in satisfactory to high yields. Unfortunately, tertbutyl esters of N-protected amino acid could not be obtained by this method. The esters (9-11) of N-protected dipeptide, Z-Gly-Gly-OR", were also synthesized in high yields by this procedure as shown in Table 1. The method is applicable to the preparation of depsipeptide. Boc-L-Ala-L-Hmb-L-Phe-OBzl (12) which is an important intermediate for the synthesis of AM-toxins, was prepared in 82% yield from Boc-L-Ala-ONSu and 1 equivalent of H-L-Hmb-L-Phe-OBzl by this method. The analytical parameters of the products obtained by this method with respect to melting point and specific rotation were identical with those of the literatures (see Ex-perimental Section). The reaction is based on a requirement for DMAP. Thus, in the absence of DMAP no reaction occurs. Probably, N-hydroxysuccinimide ester is converted to an acylpyridinium species, reactive intermediate, with DMAP. Nucleophilic attack by the alcohol on the acyl group of the acylpyridinium species generates the desired ester and DMAP, which consequently forms the salt with the resulting N-hydroxysuccinimide. Several advantages of this new procedure should be pointed out here in comparison with the known methods. The N-hydroxysuccinimide esters of N-protected amino acids are relatively stable and may be stored for ready use, and hence the esters could be easily obtained from commercial sources. This esterification procedure is very simple and proceeds under mild reaction conditions (CH2 Cl2 , at room temperature), so that labile protecting groups for other functional groups can be present. This mild and simple procedure may provide a versatile synthetic method not only for the synthesis of peptides and depsipeptides but also for the preparation of many natural products. Further studies in order to demonstrate the utility of this method are now in progress.
URI: http://hdl.handle.net/10069/16631
ISSN: 02871319
Type: Departmental Bulletin Paper
Text Version: publisher
Appears in Collections:Volume 33, No. 1

Citable URI : http://hdl.handle.net/10069/16631

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